Alzheimer disease (AD) is the most common form of dementia in the elderly. Overwhelming evidence demonstrates that the etiology of AD is a complex web of genetic and environmental factors. Early success in genetic studies has confirmed that AD risk is associated with four genes (APR, PS1, PS2, APOE), with by far the greatest proportion explained by the APOE-4 allele. However, together these genes account for less than half of the total genetic risk in AD. In contrast to this early success, finding the additional genes has been very difficult. Many studies in general outbred populations have identified numerous genomic regions of interest through linkage analysis and numerous candidate genes through association analysis. However, none of these regions or genes has yet yielded a new, confirmed, AD susceptibility gene. An alternative, complementary, and powerful approach for finding these genes is to use genetically isolated founder populations where large interrelated pedigrees can be ascertained, the environmental exposures are less variable, and the underlying genetic etiology for dementia is more homogeneous. The Amish communities of central Ohio and northern Indiana are ideal for this purpose. Over the past five years we have greatly extended our ascertainment in these communities, having already enrolled nearly 1,300 individuals and collected a wealth of clinical data. We have started genetic characterization of the Amish pedigrees through pedigree analysis, a preliminary microsatellite genome-scan, and tests of several candidate genes. Two chromosomal regions and two candidate genes have already generated interesting results. We have more than doubled the initial dataset and with advances in genomic technologies, we can take full advantage of the Amish family resource by integrating our clinical and family data with a high-density SNP panel to localize AD genes. This approach will help us accomplish our goal of identifying at least one AD gene. Our specific aims are to: 1). Continue ascertainment in the Amish communities;2). Perform a whole-genome SNP scan;3). Localize AD genes using the SNP scan data;4). Refine these minimum candidate regions and identify high priority candidate genes;and 5). Exhaustively examine these genes for association to AD in both the Amish and outbred datasets.